Analysing Anxiety. The Effects of SSRIs on Anxiety-like Behaviour: A Systematic Review & Meta-Analysis

Abstract

Abstract: Anxiety disorders are among the largest contributors to the global health related burden. Despite its high occurrence, the cause of anxiety is poorly understood. The serotonergic system appears to play a big role in the pathophysiology, which has led to the development of Selective Serotonin Reuptake Inhibitors (SSRIs) and their implementation in treatment strategies. However, the specific aspects of anxiety that are modulated by SSRIs are not yet established. Since anxiety disorders can exist on the basis of unconditioned fear, assessing anxiety in ethological paradigms could be advantageous in the endeavour of obtaining a complete understanding of the mechanism behind SSRIs. A well-rounded overview of different aspects of unconditioned anxiety can be presented through the evaluation of four anxiety tests: the Elevated Plus Maze Test (EPM), Marble Burying Test (MB), Ultrasonic Vocalisations Test (USV) and Stress-Induced Hyperthermia test (SIH). The aim of this systematic review and meta-analysis is to determine the effects of the six clinically relevant SSRIs on anxiety-like behaviour in animal studies using the EPM, MB, USV and SIH. A systematic search was conducted in PubMed and EMBASE for each anxiety test, yielding a total of 186 publications meeting inclusion criteria, of which 178 were eligible for meta-analysis. Descriptive analysis showed a great majority studying male rats and mice, with either acute or chronic SSRI treatment. Quantitative analysis revealed a significant decrease in anxiety-like behaviour in the EPM, MB and USV after SSRI administration. Additional moderator analysis through Bayesian Penalized Meta-Regression showed significant intercepts, and in the case of the MB, significant moderating influences of Human Equivalent Dose and sex. Analysis of the SIH did not yield any significant results. It can be concluded that SSRIs are effective in the treatment of various aspects of anxiety, namely approach-avoidance imbalance, obsessive compulsive tendencies and stress-induced distress calls. Furthermore, this SRMA provides insights in the optimal experimental set-up for animal research of putative anxiolytic drugs. However, additional assessment of the SIH is required to better comprehend the relation between the serotonergic system and the autonomic nervous system. Additionally, further research is needed to evaluate anxiety as it is frequently presented in the clinical setting, to gain a better understanding of interpersonal treatment responses.